Inherited mutations affecting the murine immune system have proven to be a rich source of novel genes critical to the regulation of the immune system and have furnished important animal models for human immunological disorders. These include xid, the murine equivalent of X-linked agammaglobulinemia (Thomas et al., Science 261:355, 1993; Rawlings et al., Science 261:358, 1993), beige (the equivalent of Chediak-Higashi Syndrome) (Barbosa, et al., Nature 382:262, 1996), lpr and gld (defects in fas and fas-ligand), X-linked severe combined immunodeficiency (Sugamura et al., Annu. Rev. Immunol. 14:179, 1996), and the hematopoietic cell phosphatase mutant motheaten (SHP-1) (Bignon and Siminovitch, Clin Immunol Immunopathol 73:168, 1994).
One mouse mutant of particular interest is the as-yet uncloned X-linked mouse mutant, scurfy (sf). Briefly, mice hemizygous for the scurfy mutation exhibit a severe lymphoproliferative disorder. In particular, males hemizygous (Xsf/Y) for the scurfy mutation develop a progressive lymphocytic infiltration of the lymph nodes, spleen, liver and skin resulting in gross morphological symptoms which include splenomegaly, hepatomegaly, greatly enlarged lymph nodes, runting, exfoliative dermatitis, and thickened malformed ears (Godfrey et al., Amer. J Pathol. 138:1379, 1991; Godfrey et al., Proc. Natl Acad. Sci USA 88:5528, 1991). Other clinical symptoms include elevated leukocyte counts, hypergammaglobulinemia, and severe anemia (Lyon et al., Proc. Natl. Acad. Sci. USA 87:2433, 1990); the death of affected males usually occurs by 3 weeks of age. The sf locus has been mapped to the extreme proximal region of the X chromosome, approximately 0.7 centimorgans from the locus for sparse-fur (spf) (Lyon et al., Proc. Natl. Acad. Sci. USA 87:2433, 1990; Blair et al., Mamm. Genome 5:652, 1994), itself a point mutation within the ornithine transcarbamylase gene (Otc) (Veres et al., Science 237:415, 1987). The sf locus is also tightly linked to the murine Gatal, Tcfe3, and Wasp loci (Blair et al., Mamm. Genome 5:652, 1994; Derry et al., Genomics 29:471, 1995). Similarities between scurfy and human Wiskott-Aldrich syndrome (WAS) have been noted (Lyon et al., Proc. Natl. Acad Sci USA 87:2433, 1990), and the mouse Wasp gene has been proposed as a candidate for scurfy (Lyon et al., Proc. Natl. Acad. Sci. USA 87:2433, 1990; Derry et al., Genomics 29:471, 1995). Closer biological examination reveals significant differences between WAS and scurfy, however, and the two loci have been demonstrated to be non-allelic (Jeffery & Brunkow, unpublished data). Thus, prior to applicants' invention the identity of the scurfy gene remained to be determined.
The present invention discloses methods and compositions useful for diagnosing scurfy-related diseases, as well as methods for identifying compounds which can modulate the immune system, and further provides other related advantages.